Acromegaly

Abstract

Acromegaly is an acquired disorder related to excessive production of growth hormone (GH) and characterized by progressive somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The prevalence is estimated at 1:140,000-250,000. It is most often diagnosed in middle-aged adults (average age 40 years, men and women equally affected). Due to insidious onset and slow progression, acromegaly is often diagnosed four to more than ten years after its onset. The main clinical features are broadened extremities (hands and feet), widened thickened and stubby fingers, and thickened soft tissue. The facial aspect is characteristic and includes a widened and thickened nose, prominent cheekbones, forehead bulges, thick lips and marked facial lines. The forehead and overlying skin is thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, tooth separation and jaw malocclusion. The disease also has rheumatologic, cardiovascular, respiratory and metabolic consequences which determine its prognosis. In the majority of cases, acromegaly is related to a pituitary adenoma, either purely GH-secreting (60%) or mixed. In very rare cases, acromegaly is due to ectopic secretion of growth-hormone-releasing hormone (GHRH) responsible for pituitary hyperplasia. The clinical diagnosis is confirmed biochemically by an increased serum GH concentration following an oral glucose tolerance test (OGTT) and by detection of increased levels of insulin-like growth factor-I (IGF-I). Assessment of tumor volume and extension is based on imaging studies. Echocardiography and sleep apnea testing are used to determine the clinical impact of acromegaly. Treatment is aimed at correcting (or preventing) tumor compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. Transsphenoidal surgery is often the first-line treatment. When surgery fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogs and/or radiotherapy can be used. The GH antagonist (pegvisomant) is used in patients that are resistant to somatostatin analogs. Adequate hormonal disease control is achieved in most cases, allowing a life expectancy similar to that of the general population. However, even if patients are cured or well-controlled, sequelae (joint pain, deformities and altered quality of life) often remain.

Figure 1

As compared with the hand of a normal person (left), the hand of a patient with acromegaly (right) is enlarged, the fingers are widened, thickened and stubby, and the soft tissue is thickened.

Figure 2

Facial aspect of a patient with acromegaly. The nose is widened and thickened, the cheekbones are obvious, the forehead bulges, the lips are thick and the facial lines are marked. The forehead and overlying skin is thickened, sometimes leading to frontal bossing.

Figure 3

Mandibular overgrowth leads to prognathism, maxillary widening, teeth separation and jaw malocclusion.

Figure 4

In longstanding forms, bony deformation affects the spine, with upper dorsal kyphosis and compensatory lumbar hyperlordosis. The thorax is deformed due to protuberance of the lower portion of the sternum, and by elongation and divergence of the ribs.

Figure 5

Frequent blood sampling with serum GH measurement shows that in normal subjects (left panel) GH can fluctuate between undetectable levels (most of the time) and peaks of up to 30 μg/l (90 mIU/l), owing to the episodic nature of GH secretion, while in patients with acromegaly (an example is given on right panel), GH hypersecretion is continuous and GH never returns to undetectable levels.

Figure 6

Goldman perimeter showing normal visual fields (upper panel) and bitemporlal quadranopsia due to optic chiasm compression by a pituitary adenoma (lower panel).

Figure 7

Pituitary microadenoma.

Figure 8

Pituitary macroadenoma with suprasellar extension, compressing the optic chiasm.

Figure 9

Acromegaly due to ectopic secretion of GHRH by a pancreatic tumor, metastasized to the liver (left) responsible for a pituitary hyperplasia, visible on pituitary MRI (right) and stimulation of normal somatotroph cells, leading to GH hypersecretion and acromegaly.

Figure 10

Site of action of the different therapeutic tools in acromegaly. Surgery, radiotherapy, somatostatin anlogues and dopamine agonists act at the level of the pituitary adenoma, while GH-receptor antagonists act in periphery by blocking the GH receptor and thus impairing the effects of GH on the different tissues.

Figure 11

Strategy proposed by the Authors for the current management of acromegaly. SA: somatostatin analogs; DA: dopamine agonists, GHRA: GH-receptor antagonist (pegvisomant).